Abstract
Background
Baricitinib, an oral selective JAK1/JAK2 inhibitor, is approved for the treatment of adults with severe alopecia areata (AA).
Objective
To evaluate differences in response up to week 52 among subgroups based on the baseline severity of AA assessed with the Severity of Alopecia Tool (SALT) score.
Methods
Data were pooled from BRAVE-AA1 and BRAVE-AA2, two randomized, placebo-controlled, phase 3 trials, which enrolled adults with a SALT score ≥ 50. Patients were subdivided by the degree of AA severity at baseline.
Results
Among the 855 patients treated with baricitinib 2 mg and 4 mg, improvements in scalp hair growth continued through to week 52. A superior response was observed in patients with a SALT score of 50–94 versus a score of 95–100. Patients on baricitinib 4 mg had a faster and higher response rate compared to baricitinib 2 mg.
Conclusion
Across all degrees of severity for baricitinib 2 mg and 4 mg doses, the proportion of patients responding was yet to plateau up to week 52. Response to treatment was longer for patients with a baseline SALT score 95–100. Further studies are needed to analyze other parameters that may impact observed response rates.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Why carry out this study? |
Alopecia areata (AA) is an autoimmune condition characterized by rapid hair loss. |
Extensive scalp hair loss is associated with poorer prognosis in AA; however, little is known about the actual impact of baseline severity of hair loss on treatment response with baricitinib. |
What was learned from the study? |
No meaningful difference in response to treatment was observed across the groups of patients with severe AA (SALT score 50–94). Response to treatment was delayed, and response rates were lower for patients with very severe alopecia areata (SALT score 95–100). |
These data suggest that baseline severity of hair loss should be factored into consideration when setting expectations about treatment response. |
Introduction
Alopecia areata (AA) is a chronic, autoimmune condition characterized by nonscarring hair loss with a broad spectrum of clinical presentations from localized patches to more extensive scalp hair loss [1,2,3]. While it predominantly affects the scalp, the disease can affect any hair-bearing region of the body [4, 5]. AA is associated with comorbid immune-mediated diseases (e.g., thyroid disease, lupus erythematosus, diabetes mellitus, atopic dermatitis, sinusitis, and coronary artery disease) and has psychosocial implications (e.g., anxiety, depression, and suicidality), increasing the burden of disease for patients and reducing their quality of life [6,7,8].
Extensive AA [9, 10], which includes AA subtypes such as alopecia totalis and alopecia universalis [11], is linked to poor prognosis [12]. However, there is no clear consensus on the definition of extensive or severe AA, although a threshold of at least 50% scalp hair loss is present in the scientific literature [13, 14]. Several years ago, the National Alopecia Areata Foundation (NAAF) sponsored investigation guidelines introduced severity categories based on baseline Severity of Alopecia Tool (SALT) scores, but provided no specific rationale for the proposed cut-off for groupings [15]. Building on the SALT score, AA experts developed the AA-Investigator Global Assessment (AA-IGA) [16] providing five clinical gradations of AA severity based on SALT scores, including level 3 or ‘Severe’ category for SALT ranging from 50 to 94 and Level 4 (‘Very severe’) for SALT between 95–100, representing patients with complete, or almost complete scalp hair loss. These terms help to address the ambiguity associated with previous terms used to describe extensive hair loss [13]. In parallel to the development of the AA-IGA, clinicians and patients were aligned that hair regrowth resulting in ≤ 20% scalp hair loss (i.e., at least 80% scalp hair coverage) was a successful treatment outcome for patients presenting with ≥ 50% scalp hair loss at baseline [16].
Baricitinib is an oral JAK inhibitor that primarily inhibits JAK1 and JAK2, regulating the cytokines known to promote the activation and survival of CD8(+) T cells, preventing disease development, and achieving hair regrowth [17]. Baricitinib has demonstrated efficacy and safety in treating patients with severe AA (presenting with ≥ 50% hair loss) after 36 weeks of treatment [9, 17]. Currently, baricitinib is approved for moderately to severely active rheumatoid arthritis and moderate-to-severe atopic dermatitis for adults in over 70 countries. Additionally, baricitinib has been approved in countries including the US, Europe, and Japan for adults with severe AA.
This post hoc analysis is to evaluate whether trends in response to baricitinib treatment could be observed dependent on baseline severity of scalp hair loss. For this purpose, efficacy was assessed, up to week 52, in the very severe subgroup (SALT score 95–100) and subdivisions in the severe subgroup (SALT score 50–94). These data will help physicians to discuss treatment expectations with patients based on their baseline severity at presentation.
Methods
Data are included from phase 3 cohorts of BRAVE-AA1 (NCT03570749) and phase 3 BRAVE-AA2 (NCT03899259), two randomized, double-blind, parallel-group, placebo-controlled studies evaluating the efficacy and safety of baricitinib in patients with severe AA (SALT score 50–94) and very severe AA (SALT score 95–100). Patients with a current episode of AA lasting for > 6 months to < 8 years and no spontaneous improvement (≤ 10-point reduction in SALT score) over the past 6 months were included. Additional inclusion and exclusion criteria were reported previously for both BRAVE-AA1 and BRAVE-AA2 [9]. Patients were randomized 2:2:3 to receive once-daily PBO (up to week 36) or baricitinib 2 mg or 4 mg (through to week 52). For the purpose of this analysis, the ‘severe’ group was further divided into five subgroups based on the percentage of hair loss (50–59%, 60–69%, 70–79%, 80–89%, and 90–94%). Key outcomes included the proportion of patients achieving SALT ≤ 20, SALT ≤ 10, and the percentage of SALT improvement from baseline (50% [SALT50], 75% [SALT75], and 90% [SALT90]) up to week 52.
For this exploratory post hoc analysis, frequencies and percentages were reported as descriptive statistics for categorical response variables. For the percentage’s indicative, confidence intervals were constructed using the Newcombe-Wilson method. For missing values non-responder imputation was performed. This included data collected after permanent study drug discontinuation or remotely due to the COVID-19 pandemic.
All patients provided written informed consent. Ethical review boards approved the study protocol at each study site. This study was conducted in accordance with consensus ethics principles from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, International Council for Harmonisation, and other applicable laws.
Results
Patients
Patient demographics and clinical characteristics were balanced across treatment arms and between BRAVE-AA1 and BRAVE-AA2 (Table 1). Patients were randomly assigned to PBO or baricitinib 4 mg or 2 mg. Furthermore, 89.4% (N = 338) of patients on baricitinib 4 mg and 85.7% (N = 251) of patients on baricitinib 2 mg completed 52 weeks of treatment. Patients who were non-responders on PBO at week 36 were re-randomized to baricitinib 4 mg or 2 mg and therefore do not appear in this analysis, which examined patients on continuous treatment through week 52. Of note, in the PBO cohort, the SALT ≤ 20 response rate at week 36 was low, and spontaneous regrowth was observed more frequently in the severe subgroup (13/166 [7.8%]) than in the very severe subgroup (1/178 [0.6%]) (Figure S1).
Within the baricitinib cohorts, the distribution of baseline SALT score was overall comparable between the 4 mg and 2 mg cohort (Fig. 1). The largest group in both cohorts was those with a baseline SALT score of 95–100 (baricitinib 4 mg, N = 267 [51.8%] and baricitinib 2 mg, N = 193 [56.8%]). This was followed by those with a baseline SALT score of 50–59 (baricitinib 4 mg, N = 86 [16.7%] and baricitinib 2 mg, N = 55 [16.2%]) (Fig. 1).
Efficacy Outcomes
Treatment efficacy was observed across the spectrum of disease severity, with baricitinib 4 mg consistently providing a numerically higher level of response than baricitinib 2 mg (Figs. 2, 3, 4, and S2-3; Table S1-3).
For patients with baseline SALT score 50–94 treated with baricitinib 4 mg, the efficacy over the 52 weeks was overall comparable across subgroups, with response rates at week 52 ranging from 41.5–57.6% for SALT ≤ 20 and 29.3–45.5% for SALT ≤ 10 (Figs. 2, 3; Table S1–2). The response in the SALT 95–100 cohort was characterized by a slower onset of efficacy and a lower response rate in the baricitinib 4 mg cohort at week 52 (SALT ≤ 20, 27.7%; SALT ≤ 10, 19.1%) (Figs. 2, 3). For the baricitinib 2 mg treated patients, overall comparable efficacy was observed from the SALT 50–59 cohort up to SALT 80–89 cohort, with response rates at week 52 ranging between 26.1–44.4% for SALT ≤ 20 and 17.4%-29.6% for SALT ≤ 10 (Figs. 2, 3; Table S1-2). The efficacy for patients in the SALT 90–94 subgroup was markedly lower on baricitinib 2 mg (SALT ≤ 20, 11.1%; SALT ≤ 10, 11.1%) and comparable to the SALT 95–100 group (SALT ≤ 10. 7.8%; SALT ≤ 20, 12.4%) (Figs. 2, 3; Table S1–2).
Comparable trends were observed for the various thresholds of SALT improvement from baseline. For patients treated with baricitinib 4 mg, the response rates across the different baseline SALT subgroups ranging from 50 to 94 were consistent at week 52 for the respective percentages of SALT improvement from baseline. Response rates ranged from 48.8–70.7% (SALT50), 39.0–60.6% (SALT75), and 26.8–45.5% (SALT90) at week 52 (Figs. 2, 3, 4 and S2-3; Table S3). The response in the SALT score 95–100 cohort was characterized by a slower onset of efficacy and a lower response rate in the baricitinib 4 mg cohort at week 52 for SALT50 (43.4%), SALT75 (30.0%), and SALT90 (19.1%) (Figs. 2, 3, 4 and S2-3; Table S3). For patients treated with baricitinib 2 mg and a baseline of SALT 50–89, response rates ranged from 34.8–55.6% (SALT50), 26.1–44.4% (SALT75), and 17.4–25.9% (SALT90) at week 52 (Figs. 2, 3, 4, and S2-3; Table S3). At week 52, a slower onset of efficacy and lower response rate were found in the SALT score 90–94 subgroup with response rates for SALT50 (22.2%), SALT75 (11.1%), and SALT90 (5.6%), comparable to those observed with the SALT 95–100 subgroup: SALT50 (23.8%), SALT75 (14.5%), and SALT90 (7.3%) (Figs. 2, 3, 4 and S2-3; Table S3).
Discussion
The efficacy and safety of baricitinib 4 mg and 2 mg in patients with severe and very severe AA were previously reported [9]. Here, we have investigated more precisely the impact of baseline severity on response rates over 52 weeks of continuous treatment. This extended treatment period was important to help understand whether the differences in efficacy between subgroups at earlier time points were due to differences in the time to onset of efficacy or truly reflected differences in responsiveness to treatment.
These data by baseline severity subgroups over 52 weeks of treatment confirmed the observations made on the overall cohort during the placebo period, showing superior efficacy of baricitinib 4 mg over baricitinib 2 mg for SALT ≤ 20, SALT ≤ 10, SALT50, SALT75, and SALT90 and continuous improvement over the treatment period.
When developing the AA-IGA [16], the rationale for dividing the population of patients with ≥ 50% scalp hair loss into two subgroups of SALT 50–94 and SALT 95–100 was the belief that patients with complete or almost complete scalp hair loss have a poorer prognosis. The data presented here confirm this assumption showing a lower response rate on all endpoints among the SALT 95–100 subgroup, while no particular trend was observed among the different subgroups constituting the SALT 50–94 cohort, at least when looking at baricitinib 4 mg treated patients. The lower response for all efficacy outcomes for the subgroup SALT 90–94 among baricitinib 2 mg treated patients may reflect a reduced efficacy of the baricitinib 2 mg dose in this degree of AA severity, which is not observed in the baricitinib 4 mg cohort. However, it is important to note the small sample size of this subgroup (n = 18). In addition to the lower response rate observed in the SALT 95–100 subgroup, it is also important to note the apparent delay in the onset of the response for these subjects.
These data are important for healthcare providers at the time of selecting the appropriate starting dose and setting initial treatment expectations. Understanding the different trajectories of response based on baseline disease characteristics and for the 2 mg vs. 4 mg doses may also help clinicians to make more informed choices about disease management during follow-up visits. This would hopefully lead to better patient outcomes, particularly for those with more extensive hair loss in whom response may be delayed. Improvement of AA with baricitinib treatment may reduce the psychosocial burden on patients, which exists because of the refractory disposition of AA and the previous lack of efficacious treatment options [18, 19].
Limitations of these analyses include the lack of placebo arm up to week 52. However, data from the placebo-controlled period indicate that the chance of spontaneous remission is low, particularly for the most severe patients [9]. Severity was only defined by the extent of scalp hair loss and did not consider other locations for hair loss or patient-reported outcomes. Future examination of AA severity with a multi-dimensional framework, including eyebrow, eyelash, and patient-reported outcomes, may be of significant interest in assessing the efficacy of treatment for severe forms of the disease [20, 21]. An additional limitation is that many other parameters may influence the response to treatment, including the duration of the hair loss. Patients with an episode lasting ≥ 8 years without any hair regrowth were excluded. Furthermore, the population in these phase III trials was selective, excluding patients with a previous inadequate response to oral JAK inhibitors (defined as a failure to develop significant terminal hair growth after at least 12 weeks of treatment). Thus, the contribution of these other parameters in the response to treatment remains to be determined. Finally, while the enrollment criteria were designed to limit the influence of androgenetic alopecia (male pattern Grade IV or greater using Hamilton-Norwood classification or female pattern were excluded) in overall hair loss [9], it remains possible that it partially affected the evaluation of disease severity and response to treatment.
BRAVE-AA1 and BRAVE-AA2 are ongoing and will follow patients for up to 200 weeks. Longer periods of observation may be necessary to analyze further the patterns of response to treatment based on patients' baseline characteristics and provide further guidance to clinicians. A difference was observed between response rates among patients who presented with baseline severe AA (SALT score 50–94) and those with very severe AA (SALT score 95–100). Treatment response rates through week 52 were comparable across patients with severe AA and higher than in those who presented with very severe AA. Patients with very severe AA at baseline required a longer period of treatment to achieve a SALT score ≤ 20, and the overall likelihood of treatment response may be lower in this patient subgroup, which is consistent with the less favorable prognosis reported for this cohort in the literature.
In general, there appears to be a dose-response relationship. Patients on baricitinib 4 mg had a faster and higher response rate compared to baricitinib 2 mg. These data offer insights into how patients may respond to treatment based on baseline disease severity and treatment dose, and this can help to inform patient care and management decisions.
Data Availability
Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Change history
17 November 2023
“Article note updated”.
References
Korta DZ, Christiano AM, Bergfeld W, Duvic M, Ellison A, Fu J, et al. Alopecia areata is a medical disease. J Am Acad Dermatol. 2018;78:832–4.
Pratt CH, King LE Jr, Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nat Rev Dis Primers. 2017;3:17011.
You HR, Kim SJ. Factors associated with severity of alopecia areata. Ann Dermatol. 2017;29:565–70.
Darwin E, Hirt PA, Fertig R, Doliner B, Delcanto G, Jimenez JJ. Alopecia areata: review of epidemiology, clinical features, pathogenesis, and new treatment options. Int J Trichology. 2018;10:51–60.
Lee HH, Gwillim E, Patel KR, Hua T, Rastogi S, Ibler E, et al. Epidemiology of alopecia areata, ophiasis, totalis, and universalis: a systematic review and meta-analysis. J Am Acad Dermatol. 2020;82:675–82.
García-Hernández MJ, Ruiz-Doblado S, Rodriguez-Pichardo A, Camacho F. Alopecia areata, stress and psychiatric disorders: a review. J Dermatol. 1999;26:2.
Manolache L, Benea V. Stress in patients with alopecia areata and vitiligo. J Eur Acad Dermatol Venereol. 2007;21:921–8.
Marks DH, Penzi LR, Ibler E, Manatis-Lornell A, Hagigeorges D, Yasuda M et al. The medical and psychosocial associations of alopecia: recognizing hair loss as more than a cosmetic concern.
King B, Ohyama M, Kwon OA-O, Zlotogorski A, Ko J, Mesinkovska NA et al. Two phase 3 trials of baricitinib for alopecia areata. N Engl J Med 2022;386:1687–99.
King BA, Mesinkovska NA, Craiglow B, Kindred C, Ko J, McMichael A, et al. Development of the alopecia areata scale for clinical use: results of an academic-industry collaborative effort. J Am Acad Dermatol. 2022;86:359–64.
Buckley J, Rapini RP. Totalis Alopecia. StatPearls. Treasure Island: StatPearls Publishing; 2022.
Meah N, Wall D, York K, Bhoyrul B, Bokhari L, Sigall DA, et al. The alopecia areata consensus of experts (ACE) study: results of an international expert opinion on treatments for alopecia areata. J Am Acad Dermatol. 2020;83:123–30.
Wambier CG, King BA. Rethinking the classification of alopecia areata. J Am Acad Dermatol. 2019;80: e45.
Renert-Yuval Y , Guttman-Yassky E. The changing landscape of alopecia areata: the therapeutic paradigm.
Olsen EA, Hordinsky Mk Fau-Price VH, Price Vh Fau-Roberts JL, Roberts Jl Fau-Shapiro J, Shapiro J Fau-Canfield D, Canfield D Fau-Duvic M et al. Alopecia areata investigational assessment guidelines--Part II. National Alopecia Areata Foundation. J Am Acad Dermatol 2004;51:440–7.
Wyrwich KA-OX, Kitchen HA-O, Knight SA-O, Aldhouse NA-O, Macey JA-O, Nunes FA-O, et al. The Alopecia Areata Investigator Global Assessment scale: a measure for evaluating clinically meaningful success in clinical trials. Br J Dermatol. 2020;183:702–9.
Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. 2014;20:1043-9.
Kobal I, Ramot Y. Janus kinase inhibitors for the treatment of alopecia areata. Hautarzt. 2022;73:336–43.
Lintzeri DA, Constantinou A, Hillmann K, Ghoreschi K, Vogt A, Blume-Peytavi U. Alopecia areata—Current understanding and management. J Dtsch Dermatol Ges. 2022;20:59–90.
Edson-Heredia E, Aranishi T, Isaka Y, Anderson P, Marwaha S, Piercy J. Patient and physician perspectives on alopecia areata: a real-world assessment of severity and burden in Japan. J Dermatol. 2022;49:2.
Senna M, Ko J, Glashofer M, Walker C, Ball S, Heredia EE, et al. Predictors of quality of life in patients with alopecia areata. J Invest Dermatol. 2022. https://doi.org/10.1016/j.jid.2022.02.019.
Acknowledgements
We thank all the patients and trial staff who participated in the trials.
Medical Writing and Editorial Assistance
Medical writing and editorial support were provided by Annabelle-Louise Lockey and Fionn T McSwiney, PhD, of Eli Lilly. Statistical support was provided by Helmut Petto, PhD, of Eli Lilly.
Funding
The study and the Rapid Service Fee for publication were covered by the funder (Eli Lilly and Company).
Author information
Authors and Affiliations
Contributions
Susan Taylor, Neil J. Korman, Tsen-Fang Tsai, Yukata Shimomura, Meghan Feely, Yves Dutronc, Wen-Shuo Wu, Najwa Somani and Antonella Tosti contributed to the concept and design of the trial, data analysis and/or interpretation, critical revision of the publication, and final approval to submit and were accountable for the accuracy and integrity of the publication.
Corresponding author
Ethics declarations
Conflict of Interest
Susan Taylor is an employee and is on the board of directors of Mercer Strategies. Susan Taylor is also a speaker for Beiersdorf, Inc., Evolus, Inc, MJH LifeSciences, and L'Oréal USA. Susan Taylor is on the advisory board for Beiersdorf, Inc., Biorez, Inc., Galderma Laboratories, L.P., GloGetter, Hugel America, Inc., Janssen, L'Oréal USA, Medscape/WebMD, Scientis US, and UCB. Susan Taylor is a consultant for Arcutis Biotherapeutics, Inc., Armis Scientific, Beiersdorf, Inc., Cara Therapeutics, Cara Therapeutics, Evolus, Inc., Johnson & Johnson Consumer Products Company, Piction Health, Regeneron, Vichy Laboratoires. Susan Taylor is an author for McGraw-Hill, and is on the editorial board for Practical Dermatology, Cutis, and Archives in Dermatologic Research. ST is also a peer reviewer for the British Journal of Dermatology and an investigator for Concert Pharmaceuticals, Croma-Pharma, Eli Lilly, and Pfizer. Neil J. Korman reported receiving grants and personal fees from AbbVie, Eli Lilly, Leo Pharma, Principia, and Trevi; grants from Amgen, Celgene, Chemocentryx, Dermira, Menlo Therapeutics, Syntimmune, and XBiotech; and personal fees from Genentech, Janssen, Novartis, Regeneron, Sun Pharma, and UCB. Tsen-Fang Tsai has conducted clinical trials or received honoraria for serving as a consultant for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, GSK-Stiefel, Janssen-Cilag, Leo Pharma, Merck, Novartis, Pfizer Inc., and UCB Pharma. Yukata Shimomura receives advisory fees from Eli Lilly Japan K.K. and Maruho Co. YS also receives research grants for studies not related to this work from Eli Lilly Japan K.K., Maruho Co., and Sun Pharma Japan Ltd. Meghan Feely is an associate staff member at: Mount Sinai Hospital; is a current employee and shareholder of: Eli Lilly and Company; has received consulting, travel, or speaker fees from: American Academy of Dermatology, Aerolase, Castle Biosciences, CeraVe—L'Oréal, DREAM USA, Galderma Aesthetics, Glow Recipe, La Roche-Posay—L'Oréal, Revian, Sonoma Pharmaceuticals, Sun Pharma, and Suneva Medical. Yves Dutronc, Wen-Shuo Wu, and Najwa Somani are employees, and shareholders of Eli Lilly and Company. Antonella Tosti is a compensated consultant/advisory board member for Eli Lilly, the sponsor of the study. Antonella Tosti is also a consultant for DS Laboratories, Monat Global, Almirall, Tirthy Madison, P&G, Pfizer, Myovant, Bristol Myers Squibb, Curallux LLC, and PI for Eli Lilly, Concert, and Erconia.
Ethical Approval
The trials were conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and the research protocols were approved by each center’s institutional review board or ethics committee. All patients provided written informed consent.
Additional information
Helmut Petto has now left Eli Lilly and stated that he did not want to continue as an author of this article. The omitted author cannot be contacted despite numerous efforts.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Taylor, S., Korman, N.J., Tsai, TF. et al. Efficacy of Baricitinib in Patients with Various Degrees of Alopecia Areata Severity: Post-Hoc Analysis from BRAVE AA1 and BRAVE AA2. Dermatol Ther (Heidelb) 13, 3181–3191 (2023). https://doi.org/10.1007/s13555-023-01033-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13555-023-01033-8